Certain well known narcotic analgesics belong to the class of 4,5.alpha.-epoxymorphinan compounds which have the following basic ring system, in which the atoms are numbered as indicated. ##STR2##
The two most familiar compounds of this class are morphine and its 3-methyl ether, codeine, with the structures indicated below. ##STR3##
When the 6-hydroxyl group of each of these compounds is oxidized to an oxo group, the compounds conveniently are referred to as morphinone and codeinone, respectively. When the N-methyl groups of the latter compounds are replaced by other substituent groups they may be referred to as N-substituted normorphinones and norcodeinones, respectively. There are two types of nomenclature commonly used for describing compounds herein. The trivial names, such as morphine or morphinone, are widely accepted and used for the sake of brevity and clarity. The Chemical Abstracts nomenclature is preferred and is used whereever precision is needed.
Morphine and its relatives are used primarily for the relief of pain (i.e., as analgesics). They are narcotic and possess dependence-inducing ability and produce other side effects that make them less than ideal analgesics (emesis, constipation, sweating, respiratory depressions, miosis). A compound with the appropriate profile of analgesic (agonist) and narcotic antagonist actions which is not morphine-like has potential as an analgesic agent for treatment of moderate to severe pain without liability of drug dependence. Furthermore, a compound having only strong narcotic antagonist action may be a desirable agent for treatment of drug dependence.
Bentley and Hardy disclose in Journal of the American Chemical Society, 89:13, Pp. 3267-73 certain Diels-Alder adducts of thebaine having the formula: ##STR4## where R is methyl or phenyl. It is stated that these compounds possess analgesic activity. The 6,14-endoethenotetrahydrothebaine (oripavine) series of analgesics as disclosed by Bentley and his coworkers differs from the present series by the presence of the 6,14-ethenobridge in the oripavines. This bridge alters the stereochemistry of the molecules. Furthermore, the oripavines contain a methyl ether of a tertiary alcohol at C-6 whereas the present series contains a keto group at that position. No specific data on the analgesic activity of the 7-acyl oripavines are given. The analgesic activity of the side chain tertiary alcohols in the oripavine series generally increases through R.dbd.C.sub.3 H.sub.7 and then decreases. The morphine antagonist activity for the N--CH.sub.2 --cC.sub.3 H.sub.5 derivatives decreases with the increase in the size of R.